1, 5-bis-dimethylamino-3-pentanol diethobromide



United States Patent 1,"-BIS-Dll\ IETHYLAM]NO -3 -PENTANOL DIETHOBRONIIDE Ellis, Rex Pinson, J12, and Gerald D. Laubach, Jackson Heights, N.Y., assignors to Chas. Pfizer & Co., Inc, New York, N.Y., a corporation of Delaware N0 Drawing. Filed May 19, 1955, Ser. No. 509,677

1 Claim. (Cl. 260-5676) This invention is concerned with a new class of highly efiective therapeutic agents and certain intermediates in their preparation. In particular, these compounds are the diquaternary salts of certain oxygen substituted derivatives of a group of N,N,N',N'-tetrasubstituted polymethylenediamines. I

Various agents of the diquaternary ammonium type have been suggested from time to time in the past for use in the therapy of hypertension. It has long been held that these materials function by blocking autonomic nerve impulses at the ganglia. However, recent work indicates that this may not be the only mode of action of these agents. At any rate, the diquaternary ammonium salts of this invention are distinctly superior for this type of use.

In particular, the tertiary diamino compounds from which the diquaternary salts of this invention are prepared may be represented by the following structural formula wherein Alk and Alk are straight or branch chained lower alkylene groups each having not more than six carbon atoms and such that the total number of carbon atoms in a straight chain between the two nitrogen atoms of said diamino compound is from five to eight;

and

group at least one of whose alkyl groups is a two to three carbon atom fi-hydroxyalkyl group and esters and ethers thereof, and a saturated monocyclic heterocyclic amino radical; and X is selected from the group consisting of a hydrogen atom, a lower alkyl group having ,7 not more than six carbon atoms, an aralkyl group, an

aryl group, an acyl group, an aroyl group, an N-alkylcarbamyl group, and an N-arylcarbamyl group.

In the foregoing structural formula R R R and R may, be the methyl, ethyl, propyl or isopropyl groups or v, a ,3-hydroxyalkyl group having two to three carbon atoms or an ester or ether thereof." Examples of .such groups are the B-hydroxyethyl, B-hydroxypropyl, ,B-acetogyethyl, fl-benzoxypropyl, ,B-ptopionoxyethyl, fl-butoxypropyl, js-ethoxyethyl groups, etc. R and R and R and R may also be joined toform a monocyclic sat- I urated heterocyclic amino radical such as the pyrrolidino, piperidino, or'morpholino groups. Either pair or both pairs of these'alkyl groups may be so joined to form heterocyclic groups. X is a hydrogen atom; a lower alkyl group having not more than six carbon atoms such as methyl, ethyl, butyl, or hexyl; an aralkyl group such as benzyl or benzhydryl; an aryl group such as phenyl, toluyl, or naphthyl, an acyl group such as acetyl, butyryl, or valeryl;,an aroyl group such as benzoyl, or naphthoyl, an N-alkylcarbamyl group such as N-ethylcarbamyl or N-butylcarbamyl, or an N-arylcarbamyl group such as N-phenylcarbamyl 'or' N-(u-naphthyDcarbamyl.

Alk and Alk are lower alkylene groups with straight or branched chains such as methylene, ethylene, ethylidene, propylidene, propylene, trimethylene, hexamethylene, butylene and isobutylene. They may be the same or difierent. However, Alk and Alk are so constituted that the total number of carbon atoms in a straight chain between the nitrogen atoms is from five to eightthat is the sum of the carbon atoms in a straight chain inAlk and Alk is from four to seven. This is illustrated by the follovt'ringstructural formula in which the two tertiary amino nitrogen atoms are separated by a straight chain containing five carbon atoms, and the sum of the carbon atoms in a straight chain in Alk and Alk is four.

I Conversion of these diamino compounds to the active diquaternary ammonium salts of this invention yields compounds having the structure wherein R is a lower alkyl' group having up to three carbon atoms; A is a pharmacologically acceptable anion such as iodide, chloride, bromide, sulfate, methylsulfate, acetate, propionate, tartrate, citrate, gluconate, etc., and the remaining groups having the same meaning as indicated above.

The above tertiary diamines are useful intermediates inthe preparation of the valuable diquaternary ammonium salts of this invention since treatment of them with a quaternizing agent such as an alkyl halide or sulfate yields the desired quaternary salt. Preparation of these diamines can be accomplished by a number of routes. For instance'a particularly useful process involves the reduction of a di-fl-dialkylaminoethyl ketone with lithium aluminum hydride to yield the corresponding diaminopentanol. Alternatively, the reduction may be carried out catalytically using hydrogen and a noble metal catalyst such as platinum, palladium, or rhodium. The required diamino ketone of this preparation may be prepared by the method of Cardwell and McQuillen, J. Chem. Soc., 1949, -p.- 708, and 1950, p. 1056. The complete process is illustrated by the following equations.

(CHE)2NCH2CHzHCH2CH2N(CH3)g The 'diqua-ternary ammonium salts derivable from the above diaminopentanolcon'stitute a particularly useful group of therapeutic agents for the use outlined above.-

These are 'th'e cases" where Allq and Alk of the foregoing generic formula are both ethylene groups.

The above process is readily amenable to the prep'ara-t tion. of higherhomologs by. the use oi otherchloro sub: stituted acid chlo'rid'es. For example, gamma-enterebutyryl' chloridejn theabove process yields a L's-at: 'amino-3-hexanol and delta-chlorovaleryl chloride yields a 1,7-diamino-3-heptanol; r

.An alternative route to the valuable diaminopentauol intermediate of this invention utilizes the reaction of acetonedicarboitylic acid" with an aldehyde and a secondary amine. For example, treatment of acetone dicarboxylic acid with dimethylamine and formaldehyde yields l,5-bis-dimethylamino-3-pentanol. The condensation and decarboxylation occur in a single step. The resultingketone can then be reduced as described above.

O t (cmnuomoniiioH,oniN(oH=)=+H=o+oo, Application of this reaction to other aldehydes and a secondary amine results in the; formation vof branched chained dialkylam'inoalkyl ketones which can bereduced to the corresponding useful diaminopentanol intermediates. 'Thisproces s' isrepresented below whereinR and R havethe'same meaning as before and R is a-lower alkyl or -aryl 7 group.

Aldehydes that, may be used include aliphatic aldehydes such as acetaldehyde, propioualdehyde, butyraldehyde, or isobutyraldehyde,-aromatic aldehydes such as benz aldehyde, chlorobenzaldehyde, toluic aldehyde, anaph-thaldehyde, or B-naphthaldehyde, and araliphatic aldehydes such as phenylacetaldehyde. A preferred embodiment of the invention involves the use of lower aliphatic aldehydes, that is those containing not more than five carbon atoms. a As was indicated above various secondary amines may also be employedbut, again, a pre v The above diamino alkanols may be converted to the corresponding esters or ethers by standard methods. For,

example treatment of 1,5-bis-dimethylarnino-3-pentauol with an acid anhydride such as acetic anhydride yields the acetate ester. Similarly the use of an acid chloride can be made. Examples of esters include acetates, benzoates, dichlorobenzoates, propionates, naphthoates, butyrates, etc. Ethers may be prepared bytt-reatment of the alkanol with an alkyl halide or sulfate in the presence of a strong base. ethyl, propyl, butyl, hexyl, and benzyl ethers maybe prepared. These processesare illustrated by the: 'following equations:

n V ()CHs (cnmNomoniononionnwoni OH I ferred embodiment of the invention involves theuse of those amines containing not more than threecarbon atoms in each of the alkyl groups; Ex'amplesof such amines include dime-thyl'am-iue, methylethylamine, di

ethylamine, dipropylam'ine, piperidi'ne, pyrrolidine, and

morpholine. 1 V t One useful method for carrying outthis' process involves treatment of the acetonedicarboxylic acid and the secondary amine hydrochloride in aqueous'alcoholic solution, with the aldehyde. The free amine or other acid 1 addition salt thereof may also be used. If the aldehyde is formaldehyde, it is convenient to use; absolute alcohol to dissolve the acetonedicarboxylic acid and the amine, and to use a 40% aqueous solution of formaldehyde, which is commercially. available, as the source ofthe aldehyde. The solvents that may be used in this process include those in" which all of the reactants are soluble and which will not react under the conditions employed withv the amine and'laldehyde involved. '.Materials that do not meetthese conditions includes ketones which, of course,

will react With'the, ainine and aldehyde-under the reaction conditions employed and non-polar, solvents such as aromatic and aliphatic hydrocarbons which will not dissolve the acetone dicarboxylic acid or the amine salt if a salfis employed. The lower alcohols and mixtures rai water" and: the lower alcohols have proved to be the r 7 most suitable s'olvents. By lower alcohols. ismeant those containing not more --than about iive carbon atoms.

V (CH3)zNCH2CHgCHCHzCHzN(QHr): Urethanes can be readily prepared from the above ditertiary amino carbinols very simply by treatment of them with alkyl or arylisocyanates, such as ethylisocyanate, propylisocyanate, butylisocyanate, phenylisocynate, and a-naphthylisocyanate, under anhydrous conditions. Some examples of this type of preparation are given below. 7

:1 7 rronoui rrcniorm These syntheses. are carri edfoutxby mixing the two reagents, i.e. the carbinol and the isocyauate an inert solvent such. as benzene, diethyl ether, .or dio rane. Materialsthatwill react with isocyanates such as water, and

secondary amines mus-t be'fexcluded,

Conversion. of the above diamines to theiv aluable. m -Y; a u ina-s l P t s i e t t e 2 m Thus etherssuch as the methyl,

w re.

presence or absence of a stable organic solvent.

readily by treatment with a quatemizing agent such as an alkyl halide, sulfate, or sulfonate ester either in the A few representative examples are illustrated by the following halide is precipitated and the diquaternary di-nitrate or di-acetate is formed.

A further method which is highly useful for this purpose comprises contacting the quaternary halide with a basic ion-exchange resin, preferably a highly basic compound, such as the Rohm & Haas compound Amberlite IRA-400, in the basic form. This resin is a polyquaternary ammonium compound which is prepared by chloro- -methylating a highly cross-linked copolymer of styrene and divinyl benzene and treatment of the chloromethylated material with a tertiary amine such as trimethylamine. By the use of this resin a quaternary ammonium hydroxide corresponding to a salt of this invention is formed. It is then neutralized with the appropriate acid, for instance, citric acid, tartaric acid, propionic acid, acetic acid, nitric acid, sulfuric acid, and so forth. Alternatively, the resin may be converted by means of the acid, the salt of which it is desired to convert the quaternary salt and the ion-exchange resin is then contacted with anaqueous solution of the alkyl ammonium halide. The salt may then be recovered from the eluate by a number of methods such as evaporation or solvent precipitation.

The following examples are given by way of illustration and are not intended to limit the scope of the in,- vention. In fact, many widely varying embodiments are possible without departing from the spirit and scope of the herein described invention; it is to be understood that this invention is to be limited only by the specific wording of the appended claim. In each of these examples, temperatures are given in degrees centigrade.

EXAMPLE I 1,5-bis-dimethylamin0-3-pentanol (l) A solution of 20 (0.12 mole) 1,5-bis-dimethylamino-S-pentanone in 100 ml. of absolute ether was added dropwise to a stirred solution of 50ml. of 1.24mi

lithium aluminum hydride diluted with 100 ml. of absolute ether (0.062 mole) at a rate sufiicient to cause gentle refluxing. After the addition was complete, the mixture was stirred for one hour at 25 and 5.5 ml. of water was added dropwise in order to decompose the complex and the excess lithium aluminum hydride. A buff-colored granular precipitate formed, which settled well. The ether was decanted and the precipitate washed twice by decantation with 200 ml. of ether. The ether solutions were combined, dried over anhydrous sodium sulfate and evaporated in vacuo yielding 17.52 g. of a colorless oil, which was used Without furtherpuriiication. The infrared spectrum confirmed the identity of the compound.

(2) To a cold solution of 37.8 g. (0.46 mole) of dimethylamine hydrochloride in 200 ml. absolute ethanol was added 34.0 g. (0.2 mole) of acetonedicarboxylic acid with stirring. After all the solid had dissolved 63.29 of 40% aqueous formaldehyde was added dropwise with good stirring. The solution was refluxed for 24 hours and concentrated in vacuo to about ml. The concentrate was diluted with 100 ml. of water and extracted with three 50 ml. portions of chlorofonnto remove non-basic substances. The aqueous phase was made alkaline with ml. of 30% aqueous potassium 'inabout 5 ml. of acetonitrile and treated with 2 ml.' of

ethyl bromide. The solution was kept at room temperature overnight during which time a white crystalline precipitate formed. This was collected and washed with fresh acetonitrileand recrystallized from isopropanol to give a White crystalline solid, melting point v286-287".

EXAMPLE HI 1,5-bis-dimethylamino-3 pentanol acetate One gram of 1,5-bis-dimethylamino-3-pentanol was dissolved in 3 ml. of acetic anhydride and the solution was warmed on the steam bath for 15 minutes. After standing for one hourat room temperature, 5 ml. of water was added and the solution was made strongly alkaline with saturated aqueous potassium carbonate. This mixture was diluted with 2 ml. of water and extracted three times with 20 ml. of chloroform. Concentration of the chloroform solution in vacuo left 1.65 g. of a yellow viscous oil which exhibited the typical infrared absorption spectrum of an acetate. This oil was used for the preparation of salt without further purification.

EXAMPLE IV 1,5-bis-dimethylamino 3-pentanol acetate di-ethiodide EXAMPLE v 1 1,5-bis-dime thylamin0-3-pentan0l acetate di-B-hydroxyethobromide One gram of the acetate of Example III was dissolved in '5 ml. of acetonitrile and treated with 3 ml. of B-hydroxyethylbromide. A white solid separated from the mixture after standing at room temperature for 24 hours which was collected, washed with fresh solvent and dried. The diquaternary ammonium salt was purified by recrystallization from a mixture of ethanol and acetone to yield fand ethyl acetate. The purified materialmelt 'hours, a white solid had formed. The mixture was diluted to 25 ml. with chloroformand extracted twice with of 1N hydrochloric acid. The combined acid solutions were washed with chloroform andmade strong- 'ly alkaline with saturated aqueous potassium carbonate. The oil that precipitated was taken up in chloroform, and the chloroform distilled to yield 1.04-g. of a yellow oil 5 which was not further purified.

EXAMPLE v11 I 7 1,S-bis-dimethylaniinb-3-pentanol aura-mare bnzoate di-ethobromide 1 Two grams of t e 'dichlorobenzoate 0f Exhibit; VI ';was dissolved in 7 ml. of acetonitrile and treated with 3 ml. of ethyl bromide. After standing'48 hours at roomtemperature' the precipitated solid was collected and washed with'acetonitrile. The 'crude s'alt'wa's thenpuri- 8 potassium. carbonate. .This mixture was then extracted .with chloroform and chloroform extracts concentrated in vacuo, to leave the acetate ester as a viscous yellow oil which was notfur'ther purified. A.

EXAMPLE XI 1,5-bis-dimethylamino-3-pentanol dibenzylacetdte One gram of 1,5-bisdimethylamino-3-pentanol was dissolved in 10 ml. of chloroform and 3 ml. ofdibenzylacetyl chloride was added. After standing for about 24 hours, a white precipitatehad formed. The mixture was diluted to 25 ml. with chloroform and extracted twice with 15 ml. of 1 N hydrochloric acid. The .combined acid solutions were Washed with chloroform and made strongly alkaline with saturated aqueous, potassium carbonate. The resulting pil was taken up in chloroform. Concentration of the chloroform solution yielded the product "as a yellow oil. This oil was of adequate quality for use in the preparation of saltsl The dibenzyl acetate 6rxaaip16 r warmed-1n fied by recrystallization from a mixture of isopropan'ol 1,6-bis-methylethylmrzinbq h'erafibl" I This compound was obtained by theimethylation of N,N'-diethyl-1,'6-diarnino-2 hexanol which was obtained from Carbide and Carborr Chemicals Corp. Formic edat 220 39 tallization from absolute ethanolyielded' the -purified diacid, 90%,,225 g., was added to g. .of .the diamine at 0. The resulting s olution .was heated to ,and

ml. of 38% formalin was added .dropwise. during a period of 40 minutes. Carbon dioxide 'was evolved. .The solution was refluxed for 18 hours, their cooled and acidified with 200 ml. of concentrated hydrochloric acid. The acid solution was concentrated invacuo to althick 1 EXAMPLE 1,5-bis-dimethyZamino-S-pentdyzol dibenzyl; j'

acetate dimethiodide f,

acetonitrile wit h an excess of -methyliodidefiand kept" at room temperature for several 'days duringwhich time'tlie diquafernary methiodide precipitated. Theproduct was collected, "washed with fresh solveut'and diiedl Recrysmethyliodide salt melting point 18048 2 decf i r EXAMPLE XIII;

l,5 bis-dim'ethylamirw-S-pniariol dib'er'zz'yl 1 7 5 acetate di-ethioa'id'e, v A One gram of the'dibenzyl acetateof Example was dissolved in 5 ml. of acetonitrile and treated with 3 ml.

of'ethyl iodide. After standing 24' hours at room temperature the precipitated solid was collected, washed with .,fr'esh acetonitrile and recrystallized from a mixture of syrup which was made strongly alkaline with 200 ml; of

50% aqueous sodium hydroxide. The alkaline solution was extracted four timeswith 200 ml; of chloroform, and the combined extracts evaporated leaving an amber foil which was purified by distillation. 7

EXAMPLE 'I 7 H 1,6-bis-methylethylamina-Z-hexanol dimethosulfate One gram of the hexanol of Example VI II was dis- 7 solvedin 5 ml. of tetrahydrofuran and treated with 2 ml.

of dimethylsulfate. A slight evolution of heat was obwarmed on the steam bath for about one hal-f hour. After standing. for about-three hours at room tempera- A ture 5 ml. of Water was addedand' the solution was made m alkali-Herb) llt with sat rated; aqueous @(1942), page 745,

ethanol and isopropanol to give the purified salt. Melting point 1638-1646 dec.

What is claimed is: A 1,5-bis-dimethylamino-3-pentanol diethobromide.

References Cited in the file of this patent UNITED STATES PATENTS 2,113,606 Taub Apr. 12, 1938 50 2,532,277 Castle Dec. 2', 1950 2,636,051 Whetstone et -al'.- Apr. 21, -3

7 FOREIGN PATENTS y i 30,315 Austria 1 .ocr. 2 5,1907 56 517,147 Belgium Feb. 14,1953 669,823 Germany Jan. 5, 1939 7 OTHER REFERENCES 7 V 1 Ingold'et al.: J. Chemsoc. ,(London), 1931,v pages 1669-76.

' Aurisicchio: Indus'tria Chimica, vol. 8 (1933), pages 442-44.

Gibson et al;: 165;-'17l-72. Q v A Beilsteinzi Org'anische Chemie, ver

see sns slxl rages 

